Scientific Abstract Idiopathic inflammatory myositis (IIM) is a heterogeneous group of systemic disorders characterized by inflammation in the muscle and other organs. Unfortunately some patients are refractory to currently available treatment options. This has led to the exploration of novel therapies for IIM. Several lines of evidence support a role for B cells in the pathogenesis of IIM and because high levels of the B cell survival cytokine BAFF (B cell activating factor) are found in the serum and muscle of affected patients, BAFF inhibition is considered a relevant therapeutic approach. The goal of this proposal is to characterize the mechanism of action of belimumab, a potential new therapeutic for myositis, in patients being treated in the setting of a funded multicenter randomized placebo controlled clinical trial. The ancillary studies proposed here are based on the hypotheses that belimumab will target nave B cells and IFN driven autoimmune plasmablast responses and will, either directly or indirectly decrease systemic inflammation and T cell and monocyte activation. Technologies will include detailed phenotyping of immune cells including B cells, T cells and myeloid cells, analysis of immunoglobulin gene repertories, multiplex analyses of cytokines, effects of drug on the interferon signature and transcriptional profiling of selected cell subsets. Each subject will act as their own control and samples will be collected at intervals throughout the trial. Results will also be compared to those of similar assays we are performing in SLE patients to determine whether there are differences in responses to belimumab between the two diseases. These studies should shed new light on the mechanism of action of belimumab in the setting of muscle inflammation and may help us to understand which myositis patients may benefit from this therapy.